Pramipexole is a known dopamine D2 receptor agonist. It is structurally different from the ergot-derived drugs, for example, such as bromocriptine or pergolide. It is a full agonist of dopamine, with receptor selectivity for dopamine D2 family.
Pramipexole is designated chemically as (S)-2-Amino-4,5,6,7-tetrahydro-6-(propylamino) benzothiazole, and has molecular formula C10H17N3S and a relative molecular weight of 211.33. The chemical formula is as follows:

Pramipexole salt generally used is pramipexole dihydrochloride monohydrate (pramipexole dihydrochloride monohydrate) (molecular formula C10H17N3S; relative molecular weight of 302.27). Pramipexole dihydrochloride monohydrate is a white to yellow-white, odorless, crystalline powder. Melting occurs in the range of 296° C. to 301° C., with decomposition. Pramipexole is a chiral compound with a chiral center.
In 1997, pramipexole immediate release (IR) tablet is first approved in the United States. Subsequently, marketing authorized in the European Union, Switzerland, Canada, South America, the countries in Eastern Europe and Asia. Pramipexole dihydrochloride monohydrate is highly soluble compound. Water-solubility of Pramipexole is greater than 20 mg/ml, a solubility in a pH 2 to pH 7.4 buffer media is generally higher than 10 mg/ml. Pramipexole dihydrochloride monohydrate is non-hygroscopic, having high crystalline nature. Crystal modification (monohydrate) of pramipexole does not change under grinding. Pramipexole in the solid state is very stable, and its solution is light sensitive.
A clinical study has shown that pramipexole immediate release tablet formulation combined with levodopa could be used for the treatment of signs and symptoms of Parkinson's disease in the early or advanced stages. IR tablet has to be taken three times a day. The results of three clinical experiments such as a multiple center, randomized double-blind comparison, placebo-controlled experiment have shown that, in the case of administering levodopa to treat early Parkinson's patient, simultaneously administering pramipexole extended release tablet with daily dose increasing from 0.375 mg to 3 mg. At 18 weeks of treatment, UPDRS score is −8.1 for the treatment group, and −5.1 for the placebo group, there is a statistical difference between the two groups. At 33 weeks of treatment, UPDRS score is −8.6 for the treatment group, and UPDRS score is −3.8 for the placebo group, treating effect is not caused by ages or sex according to the course of the study. For patients with advanced Parkinson's disease, there are the fluctuations of movement staying in the “off” state for at least 2 h every day. When administering levodopa with pramipexole simultaneously, a dosage with starting dose of 0.375 mg, gradually increased to 4.5 mg within 7 weeks, and then administering for 26 weeks continuously according to the efficacy and tolerability of the treated subject. The dose of levodopa shall be reduced, in case of adverse reaction of dopaminergic drug occurred. At 18 weeks of treatment, UPDRS score is −11.0 for the treatment group, and UPDRS score is −6.1 for the placebo group. The regulation change of the “off” state for treatment group is −2.1 h, and −1.4 h for that of the placebo group. At 33 weeks of treatment, UPDRS score is −11.1 for the treatment group, and UPDRS score is −6.8 for the placebo group. In view of the pharmacokinetic point, pramipexole IR tablet are able to be completely and rapidly absorbed after oral administration. Its absolute bioavailability is greater than 90%, and the maximum plasma concentration occurs from 1 to 3 hours. Food intake shall influence absorption of pramipexole. Pramipexole displays linear kinetic characteristics, and its changes in plasma level of patients are relatively smaller. The elimination half-life of pramipexole is 8 hours for young people, 12 hours for elder people.
It is well known, the improvement of the active ingredient release allows to simplify the patient's dosing regime by reducing the amount of the daily intake, improving patient's compliance and reducing site effect. Pramipexole extended release tablet formulation is able to meet requirements for the therapeutic effect and capable of reducing the side effect.
A number of prior arts is to provide a composition of the extended release tablet formulation and manufacturing methods thereof.
A sustained-release pharmaceutical composition in form was disclosed in WO 2004/010997, comprising water-soluble salt of pramipexole dispersing in a matrix comprising a hydrophilic polymer and a pregelatinized starch, wherein tensile strength of the said starch is at least 0.15 kN cm−2, preferably at least 0.175 kN cm−2, more preferably at least 0.2 kN cm−2.
According to a preferred embodiment of the invention, there is provided an oral pharmaceutical composition in a tablet form, the tablet containing a core dispersed in the matrix comprising an amount of about 0.375, 0.75, 1.5, 3.5 or 4.5 mg pramipexole dihydrochloride monohydrate, the matrix comprising (a) HPMC type 2208 in an amount of about 35 to 50% of the tablet by weight, and (b) pre-gelatinized starch with a tensile strength of at least 0.15 kN cm−2 in a solid composition of 0.8, in an amount of about 45 to 65% by weight of the tablet, wherein the core is substantially encapsulated in a coating layer in an amount of approximately 2-7% of the tablet by weight, comprising a hydrophobic cellulose and the insoluble component, and pore-forming HPMC component. However, the question raised is that: the artican does not know if the release rate of the composition of a pramipexole extended release tablet according to the above-mentioned invention, is the same or different at different pH values.
Chinese Patent CN101005830 B discloses a composition of pramipexole extended release tablet formulation in an orally dosing form comprising pramipexole or a pharmaceutically acceptable salt thereof dispersed in a matrix, said matrix comprising water swelling polymer of at least two non-pregelatinized starch, one of which is an anionic polymer, preferably is an acrylic polymer, more preferably is a carbomer, in an amount of about 1-10% by weight of the tablet, another one water swelling polymer of the non-pregelatinized starch is a neutral polymer, preferably is hydroxypropyl cellulose, more preferably is hydroxypropyl methylcellulose, in amount of about 25-65% by weight of the tablet. Although the said invention discloses a composition of pramipexole extended release tablet formulation, the active ingredients of the pharmaceutical composition have shown the release characteristics is associated with the pH value, i.e. showing different release rate under the condition of at the same time and at different pH value.
To the inventor's understanding, there is no prior art to disclose a composition of pramipexole extended release tablet formulation to display a pH-independent release profile in the range of pH 1 to pH 7.5, prior to the present invention.